ABSTRACT: Alzheimer's disease (AD) is a progressive degenerative disease of the brain characterized by loss of memory and cognitive function. There is no cure for AD. The worldwide prevalence of AD was 46.8 million in 2015 and is expected to increase to 131.5 million by 2050. Therapeutic strategies to date have had very limited success in slowing the progression of the disease. The potential beneficial impact of exercise on AD disease is well known. Interestingly however in experiments in a mouse model of AD, decreased exercise activity measured by voluntary wheel running precedes the onset of plaque development. In our currently funded NIA PPG we have shown that kynurenine a tryptophan oxidation product that accumulates with age results in loss of both bone and muscle mass. We have highlighted some of these links in a recently co-edited (Hamrick and Isales) special issue in Experimental Gerontology: The Kynurenine Pathway in Aging. Further, kynurenine has also been implicated in AD progression and depression. A majority of kynurenine (60%) in the brain comes from peripheral sources and lowering circulating kynurenine levels through exercise or activation of muscle PGC 1 alpha (in essence an exercise mimetic) lowers circulating kynurenine levels by conversion to kynurenic acid (KNA which does not cross the blood brain barrier) and protects against depression. We submitted an AD supplemental request last year, which was not funded. In the current supplemental application, we submit a less ambitious experimental plan whose purpose is to generate the preliminary data to then submit a full RO1 application. Same approach to not only slow AD progression but also prevent bone and muscle loss in the AD model. In this proposal we will use a PCG 1 alpha inducer, ZLN005 and compare its effects to those of exercise (voluntary wheel running). Thus, the specific aims for this one- year supplement are: Specific Aim #1: Test the hypothesis that placing the AD mice on ZN005, compared to daily exercise, will be beneficial in slowing AD progression. Specific Aim #2: Test the hypothesis that, ZN005 will protect against muscle loss seen with AD onset by lowering circulating kynurenic acid levels.